A three-pronged approach to gaining information about transmembrane signalling of growth hormone (GH) receptor will be taken. 1) Based on the finding that binding of GH to the GHBP/receptor is followed by binding of a second molecule of GHBP/receptor to a secondary site on GH ("ligand-induced dimerization"), it is hypothesized that receptor dimerization is the first step in signal transduction. Accordingly, the binding interface of the receptor (and/or that of GH) will be mutated to prevent dimerization, and the biological activity of the mutant receptor and/or ligand will be measured. 2) The intracellular domain of the GH receptor will be expressed in both monomeric and dimeric form. It will then be used as an affinity reagent to. identify proteins binding to the intracellular receptor domain. Such proteins are expected to correspond to proteins recruited to the receptor during signalling (e.g., tyrosine kinases). Proteins with high affinity binding will be cloned. 3) Naturally occurring mutant GH receptors with presumed mutations in areas not involved in GH binding (obtained from "Laron dwarfs" who have normal GH binding to GHBP) will be amplified, subcloned and sequenced to derive information about region /sites that are critical for signal transduction.